Guanidine Derivatives and Therapeutic Uses Thereof

ABSTRACT

Compounds of the formula (I):  
                 
 
     in which the radicals R and R 1  to R 10  are as defined in the description, processes for the preparation of them, use thereof for the treatment of cardiovascular diseases, and pharmaceutical compositions comprising them.

The present invention relates to guanidine derivatives, to processes for the preparation of these derivatives, to pharmaceutical compositions comprising these derivatives, and to the use of these derivatives as CETP repressors, for the prevention and treatment of cardiovascular diseases, and in particular atherosclerosis and type II diabetes.

Atherosclerosis, and cardiovascular diseases in general, are one of the main causes of death in developed countries. Despite the efforts directed towards minimising the risk factors, such as smoking, a sedentary lifestyle and an unbalanced diet, and also the therapeutic treatments for dyslipidaemia using pharmaceutical compositions, death due to myocardial infarction and other cardiovascular diseases remains very high.

It has been demonstrated that the risks of cardiovascular diseases are highly dependent on the levels of low-density lipoproteins (LDL) in the blood plasma.

Whereas high levels of triglycerides and of LDL cholesterol contribute positively to the risks of developing cardiovascular diseases, high levels of high-density lipoprotein (HDL) cholesterol reduce the risks of developing these diseases. Thus, dyslipidaemia does not have only one risk profile for cardiovascular diseases, but may include one or more lipid dysfunctions.

Among the many factors acting on the levels of triglycerides, LDL and HDL, CETP (cholesteryl ester transfer protein) plays an important role. CETP catalyses the transfer and exchange of triglycerides and of cholesterol esters between the HDLs of the plasma and the low-density lipoproteins (LDL) and very-low-density lipoproteins (VLDL) which contain triglycerides. If the action of CETP on the levels of these various lipids contained in the lipoproteins is increased, it is thus considered as being pro-atherogenic, in particular in the case of individuals in whom the lipid profile represents a high risk of cardiovascular diseases.

Thus, modulating the activity of CETP, either by direct inhibition or by controlled regulation of CETP expression, may be considered as a possible means of therapeutic treatment (see, for example, Kushwaha et al., J. Lipid Research, 34, (1993), 1285-1297).

Accordingly, a considerable amount of research has been directed towards CETP inhibitors, and has given rise to inhibitors of peptide and non-peptide type. Among the latter, mention may be made of CETP inhibitors of tetrahydroquinoline type (described in patent application EP-A-0 818 448) or those of 2-arylpyridine type (EP-A-0 796 846), or alternatively those described in patent application EP-A-0 818 197, to mention but a few.

Despite the existence in the literature of all these inhibitors, there is nevertheless still a need for novel CETP inhibitors that are more effective, that have a longer duration of action, are more specific, show better absorption and better solubility and have fewer risks of side effects.

The present invention proposes to achieve these objectives, in total or in part, by means of novel compounds of guanidine structure.

More specifically, the invention relates to guanidine derivatives of the formula (I):

in which:

-   R¹ is chosen from a hydrogen atom and a (C₁-C₆)alkyl radical, or     alternatively     -   the two radicals R¹ form, together with the carbon atom that         bears them, a (C₃-C₁₀)cycloalkyl radical; -   R² is chosen from a (C₁-C₁₀)alkyl radical, a (C₂-C₁₀)alkenyl     radical, a (C₆-C₁₈)aryl(C₁-C₁₀)alkyl radical, a     (C₁-C₆)alkyl-O—(C₁-C₁o)alkyl radical and a     (C₃-C₁₀)cycloalkyl(C₁-C₁₀)alkyl radical; -   R³ and R⁴, which may be identical or different, are chosen     independently from a hydrogen atom, a (C₁-C₁₀)alkyl radical, a     (C₂-C₁₀)alkenyl radical, a (C₆-C₁₈)aryl(C₁-C₁₀)alkyl radical, a     (C₁-C₆)alkyl-O—(C₁-C₁₀)alkyl radical and a     (C₃-C₁₀)cycloalkyl(C₁-C₁₀)alkyl radical, or alternatively R³ and R⁴     form, together with the nitrogen atom that bears them, a 3- to     9-membered heterocycle; -   R⁵, R⁶, R⁷ and R⁸, which may be identical or different, are chosen     independently from a hydrogen atom, a (C₁-C₁₀)alkyl radical, a     (C₁-C₁₀)-alkenyl radical and a (C₁-C₆)alkyl-O— radical; and -   R⁹ and R¹⁰, which may be identical or different, are chosen     independently from a hydrogen atom and a (C₁-C₆)alkyl radical, or     alternatively R⁹ and R¹⁰ form, together with the nitrogen atom that     bears them, a 3- to 7-membered heterocycle;

the optical and geometrical isomers, oxide forms and tautomeric forms thereof, and also the pharmaceutically acceptable addition salts thereof with acids or bases.

The acids that can be used for the formation of salts of compounds of the formula (I) are mineral or organic acids. The resulting salts are, for example, the hydrochlorides, hydrobromides, sulfates, hydrogen sulfates, dihydrogen phosphates, citrates, maleates, fumarates, trifluoroacetates, 2-naphthalenesulfonate and para-toluenesulfonate.

The bases that can be used for the formation of salts of compounds of the formula (I) are organic or mineral bases. The resulting salts are, for example, the salts formed with metals and especially alkali metals, alkaline-earth metals and transition metals (such as sodium, potassium, calcium, magnesium or aluminium) or with bases, for instance ammonia, or secondary or tertiary amines (such as diethylamine, triethylamine, piperidine, piperazine or morpholine) or with basic amino acids, or with osamines (such as meglumine) or with amino alcohols (such as 3-aminobutanol and 2-aminoethanol).

The invention especially covers the pharmaceutically acceptable salts, but also salts allowing a suitable separation or crystallisation of the compounds of the formula (I), such as the salts obtained with chiral amines or with chiral acids.

Examples of chiral amines that can be used include quinine, brucine, (S)-1-(benzyloxymethyl)propylamine (III), (−)-ephedrine, (4S,5R)(+)-1,2,2,3,4-tetramethyl-5-phenyl-1,3-oxazolidine, (R)-1-phenyl-2-p-tolylethylamine, (S)-phenylglycinol, (−)-N-methylephedrine, (+)(2S,3R)-4-dimethylamino-3-methyl-1,2-diphenyl-2-butanol, (S)-phenylglycinol and (S)-α-methylbenzylamine, or a mixture of two or more thereof.

Examples of chiral acids that can be used include (−)-D-di-O-benzoyltartaric acid, (−)-L-di-O-benzoyltartaric acid, (−)-di-O,O′-p-toluyl-L-tartaric acid, (+)-di-O,O′-p-toluyl-D-tartaric acid, (R)(+)-malic acid, (S)(−)-malic acid, (+)-camphanic acid, (−)-camphanic acid, R(−)-1,1′-binaphthalene-2,2′-diyl hydrogen phosphate acid, (S)(+)-1,1′-binaphthalene-2,2′-diyl hydrogen phosphate acid, (+)-camphoric acid, (−)-camphoric acid, (S)(+)-2-phenylpropionic acid, (R)(−)-2-phenylpropionic acid, D-(−)-mandelic acid, L-(+)-mandelic acid, D-tartaric acid and L-tartaric acid, or a mixture of two or more thereof.

The chiral acid is preferably chosen from (−)-di-O,O′-p-toluyl-L-tartaric acid, (+)-di-O,O′-p-toluyl-D-tartaric acid, (R)(−)-1,1′-binaphthalene-2,2′-diyl hydrogen phosphate acid, (S)(+)-1,1′-binaphthalene-2,2′-diyl hydrogen phosphate acid, D-tartaric acid and L-tartaric acid, or a mixture of two or more thereof.

The invention also covers the optical isomers, in particular stereoisomers and diastereoisomers, where appropriate, of the compounds of the formula (I), and also mixtures of optical isomers in any proportion, including racemic mixtures.

The geometrical isomers, commonly referred to as cis and trans, or alternatively E and Z, are also included in the field of the present invention, in pure forms, or as mixtures in any proportion.

Depending on the nature of the substituents, the compounds of the formula (I) may also be in various tautomeric forms that are also included in the present invention, alone or as mixtures of two or more of them, in any proportion.

By way of example, if R³ represents hydrogen, the compound of the formula (I) may be in the tautomeric form (I_(T)) below:

The tautomeric form (I_(T)) should be understood as forming an integral part of the compounds of the formula (I).

The compounds of the formula (I) above also comprise the prodrugs of these compounds.

The term “prodrugs” means compounds which, once administered to the patient, are chemically and/or biologically converted by the live body into compounds of the formula (I).

In the description hereinbelow, the term “(C₁-C₁₀)alkyl radical” means a linear or branched hydrocarbon-based chain containing from 1 to 10 carbon atoms, optionally substituted by one or more groups G defined below.

Examples of (C₁-C₁₀)alkyl radicals are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, methylbutyl, ethylpropyl, hexyl, isohexyl, neohexyl, methylpentyl, dimethylbutyl, ethylbutyl, methylethylpropyl, heptyl, methylhexyl, propylbutyl, dimethylpentyl, octyl, methylheptyl, dimethylhexyl, nonyl, decyl, methylnonyl, dimethyloctyl and dodecyl.

The term “(C₁-C₆)alkyl radical” means a linear or branched hydrocarbon-based chain containing from 1 to 6 carbon atoms, optionally substituted by one or more groups defined below.

Examples of (C₁-C₆)alkyl radicals are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, methylbutyl, ethyl-propyl, hexyl, isohexyl, neohexyl, methylpentyl, dimethylbutyl, ethylbutyl, and methylethylpropyl.

The term “(C₁-C₆)alkoxy radical” should be understood as being a (C₁-C₆)alkyl radical linked to a divalent oxygen atom.

The term “(C₃-C₁₀)cycloalkyl radical” denotes a mono-, bi- or poly-cyclic hydrocarbon-based radical containing from 3 to 10 carbon atoms. Examples of C₃-C₁₀ cycloalkyl radicals are especially cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclodecyl radicals.

The term “(C₂-C₁₀)alkenyl radical” means an aliphatic hydrocarbon-based group containing one or more unsaturations of vinyl type. Examples of alkenyl radicals are vinyl, prop-2-enyl, but-2-enyl, but-3-enyl, pent-2-enyl, pent-3-enyl, pent-4-enyl, 3-methylbut-2-enyl, hex-5-enyl, 4-ethylhex-3-enyl and the like.

Still within the context of the present invention, the term “(C₆-C₁₈)aryl radical” means a mono-, bi-or polycyclic carbocyclic aromatic radical containing from 6 to 18 carbon atoms. Aryl radicals that may be mentioned include phenyl, naphthyl, anthryl and phenanthryl radicals.

The heterocyclic radicals are monocyclic, bicyclic or polycyclic groups comprising one or more hetero atoms generally chosen from O, S and N, optionally in oxidising form (in the case of S and N).

Preferably, at least one of the monocycles constituting the heterocycle comprises from 1 to 4 endocyclic hetero atoms and better still from 1 to 3 endocyclic hetero atoms chosen from O, N and S.

According to the invention, the heterocyclic polycyclic nucleus consists of one or more monocycles that are each 5- to 8-membered.

The heterocyclic groups are saturated, partially unsaturated, totally saturated or aromatic.

Examples of 5- to 8-membered monocyclic aromatic heterocyclic groups are heteroaromatic groups derived from pyridine, furan, thiophene, pyrrole, imidazole, thiazole, isoxazole, isothiazole, furazane, pyridazine, pyrimidine, pyrazine, thiazines, oxazole, pyrazole, oxadiazole, triazole and thiadiazole.

Preferred heteroaryl radicals that may be mentioned include pyridyl, pyrimidinyl, triazolyl, thiadiazolyl, oxazolyl, thiazolyl and thienyl radicals.

Examples of bicyclic heteroaryls in which each monocycle is 5- to 8-membered include indolizine, indole, isoindole, benzofuran, benzothiophene, indazole, benzimidazole, benzothiazole, benzofurazane, benzothiofurazane, purine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, naphthyridines, pyrazolotriazine (such as pyrazolo-1,3,4-triazine), pyrazolopyrimidine and pteridine.

Preferred heteroaryl radicals that may be mentioned include quinolyl, pyridyl, benzothiazolyl and triazolyl radicals.

Tricyclic heteroaryls in which each monocycle is 5- to 8-membered are chosen, for example, from acridine, phenazine and carbazole.

The partially or totally saturated heterocyclic groups, or the unsaturated heterocyclic groups, are heterocyclic groups bearing no unsaturations, or comprising one or more unsaturations derived from the aromatic heterocyclic groups defined above, respectively.

Saturated or unsaturated monocyclic 5- to 8-membered heterocycles are the saturated or, respectively, the unsaturated derivatives of the aromatic heterocycles.

More particularly, mention may be made of morpholine, piperidine, thiazolidine, oxazolidine, tetrahydrothienyl, tetrahydrofuranyl, pyrrolidine, isoxazolidine, imidazolidine or pyrazolidine.

The various aryl and heterocyclic groups and radicals defined in the present description are optionally substituted by one or more of the following radicals G:

trifluoromethyl; styryl; a halogen atom; a monocyclic, bicyclic or tricyclic aromatic heterocyclic radical comprising one or more hetero atoms chosen from O, N and S; and optionally substituted by one or more radicals T as defined below; a group Het-CO— in which Het represents an aromatic heterocyclic radical as defined above optionally substituted by one or more radicals T; nitro; cyano; (C₁-C₁₀)alkyl; (C₁-C₁₀)alkylcarbonyl; (C₁-C₁₀)alkoxycarbonyl-A- in which A represents (C₁-C₆)alkylene, (C₂-C₆)alkenylene or a bond; (C₃-C₁₀)cycloalkyl; trifluoromethoxy; di(C₁-C₁₀)alkylamino; (C₁-C₁₀)alkoxy(C₁-C₁₀)alkyl; (C₁-C₁₀)-alkoxy; (C₆-C₁₈)aryl optionally substituted by one or more radicals T; (C₆-C₁₈)-aryl(C₁-C₁₀)alkoxy-(CO)_(n)— in which n is 0 or 1 and aryl is optionally substituted by one or more radicals T; (C₆-C₁₈)aryloxy(CO)_(n)— in which n is 0 or 1 and in which aryl is optionally substituted by one or more radicals T; (C₆-C₁₈)arylthio in which aryl is optionally substituted by one or more radicals T; (C₆-C₁₈)aryloxy-(C₁-C₁₀)alkyl(CO)_(n)— in which n is 0 or 1 and in which aryl is optionally substituted by one or more radicals T; a saturated or unsaturated, monocyclic 5- to 8-membered heterocycle comprising one or more hetero atoms chosen from O, N and S, optionally substituted by one or more radicals T; (C₆-C₁₈)arylcarbonyl optionally substituted by one or more radicals T; (C₆-C₁₈)arylcarbonyl-B-(CO)_(n)— in which n is 0 or 1; B represents (C₁-C₆)alkylene or (C₂-C₆)alkenylene and aryl is optionally substituted by one or more radicals T; (C₆-C₁₈)aryl-C-(CO)_(n)— in which n is 0 or 1, C represents (C₁-C₆)alkylene or (C₂-C₆)alkenylene and aryl is optionally substituted by one or more radicals T; (C₆-C₁₈)aryl fused to a saturated or unsaturated heterocycle as defined above, optionally substituted by one or more radicals T; (C₂-C₁₀)alkynyl; T is chosen from a halogen atom; (C₆-C₁₈)-aryl; (C₁-C₆)alkyl; (C₁-C₆)alkoxy; (C₁-C₆)alkoxy(C₆-C₁₈)aryl; nitro; carboxyl; (C₁-C₆)alkoxycarboxyl; and T may represent oxo in the case where it substitutes a saturated or unsaturated heterocycle; or T represents (C₁-C₆)alkoxycarbonyl-(C₁-C₆)alkyl; or (C₁-C₆)alkylcarbonyl((C₁-C₆)alkyl)_(n)— in which n is 0 or 1.

If two vicinal carbon atoms are substituted, T may represent a C₁-C₆ alkylenediyl chain or a C₁-C₆ alkylenedioxy chain.

The term “halogen atom” means a chlorine, bromine, iodine or fluorine atom.

The term “alkylenediyl chain” means a divalent radical of linear or branched aliphatic hydrocarbon-based type derived from the alkyl groups defined above by abstraction of a hydrogen atom. Preferred examples of alkylenediyl chains are chains —(CH₂)_(k)— in which k represents an integer chosen from 2, 3, 4, 5 and 6 and chains >C(CH₃)₂ and —CH₂—C(CH₃)₂—CH₂—. The alkylenedioxy chains denote chains —O—Alk-O— in which Alk represents linear or branched alkylene, it being understood that alkylene is as defined above for alkylenediyl. Preferred meanings of —O—Alk-O— are, for example, —O—C(CH₃)₂—O or —O—CH₂—CH₂—O—.

The term “alkenylene” is defined as an unsaturated alkylene chain containing one or more ethylenic unsaturations, preferably 1 to 3 ethylenic unsaturations. Examples of alkylene chains are —CH═CH— or —CH═CH—CH═CH—.

The term “alkynyl” means an aliphatic hydrocarbon-based group containing one or more unsaturations of acetylenic type. A preferred example is HC≡C—.

The preferred compounds are those of the formula (I) in which the alkyl radicals optionally present are unsubstituted or monosubstituted, and, in this case, more preferably w-monosubstituted.

A first preferred subgroup of the compounds of the invention consists of compounds for which R⁸ represents hydrogen, the other substituents being as defined above.

A second preferred subgroup of the compounds of the invention consists of compounds for which R⁷ represents hydrogen, the other substituents being as defined above.

A third preferred subgroup of the compounds of the invention consists of compounds for which R⁶ represents hydrogen, the other substituents being as defined above.

A fourth preferred subgroup of the compounds of the invention consists of compounds for which R⁵ represents hydrogen, the other substituents being as defined above.

A fifth preferred subgroup of the compounds of the invention consists of compounds for which R¹ represents hydrogen or a (C₁-C₆)alkyl and preferably (C₁-C₃)alkyl radical, more preferably methyl, the other substituents being as defined above.

A sixth even more preferred subgroup of the compounds of the invention consists of compounds for which R² is chosen from an unsubstituted (C₁-C₁₀)alkyl radical, an w-monosubstituted (C₁-C₁₀)alkyl radical, a (C₂-C₁₀)alkenyl radical, a (C₆-C₁₈)aryl(C₁-C₁₀)alkyl radical, preferably phenyl-(C₁-C₁₀)alkyl, more preferably benzyl, more preferentially unsubstituted or monosubstituted on the aromatic nucleus, a (C₁-C₆)alkyl-O—(C₁-C₁₀)alkyl radical and a (C₃-C₁₀)cycloalkyl(C₁-C₁₀)alkyl radical, preferably (C₃-C₆)-cycloalkyl(C₁-C₁₀)alkyl, the other substituents being as defined above.

A seventh preferred subgroup of the compounds of the invention consists of compounds for which R⁹ and R¹⁰ are identical and each represent a hydrogen atom or a (C₁-C₆)alkyl radical, preferably a methyl radical, the other substituents being as defined above.

An eighth preferred subgroup of the compounds of the invention consists of compounds for which R³ and R⁴ each represent a (C₁-C₆)alkyl radical, or R³ represents a hydrogen atom and R⁴ represents a (C₁-C₁₀)alkyl radical, or alternatively R³ and R⁴ form, together with the nitrogen atom that bears them, a 5- or 6-membered heterocycle, the other substituents having the definitions given above.

The compounds of the formula (I) that are also preferred are those having one or more of the following characteristics, taken separately or in combination:

-   R¹ represents a hydrogen atom or a methyl radical; -   R² is chosen from an unsubstituted (C₁-C₁₀)alkyl radical, an     ω-mono-substituted (C₁-C₁₀)alkyl radical, a (C₂-C₁₀)alkenyl radical,     a phenyl-(C₁-C₁₀)alkyl radical, preferably benzyl, more preferably     unsubstituted or monosubstituted on the aromatic nucleus, a     (C₁-C₆)alkyl-O—(C₁-C₁₀)alkyl radical and a     (C₃-C₆)cycloalkyl(C₁-C₁₀)alkyl radical; -   R³ and R⁴ each represent a (C₁-C₆)alkyl radical, or alternatively R³     represents a hydrogen atom and R⁴ represents a (C₁-C₁₀)alkyl     radical, or alternatively R³ and R⁴ form, together with the nitrogen     atom that bears them, a 5- or 6-membered heterocycle; -   R⁵ represents hydrogen; -   R⁶ represents hydrogen; -   R⁷ represents hydrogen; -   R⁸ represents hydrogen; -   R⁹ and R¹⁰, which are identical, each represent a hydrogen atom or a     methyl radical.

According to one most particularly preferred embodiment of the present invention, the compounds of the formula (I) are those for which:

-   R¹ represents a hydrogen atom or a methyl radical; -   R² is chosen from an unsubstituted (C₁-C₁₀)alkyl radical, an     ω-mono-substituted (C₁-C₁₀)alkyl radical, a (C₂-C₁₀)alkenyl radical,     a phenyl-(C₁-C₁₀)alkyl radical, preferably benzyl, more preferably     unsubstituted or monosubstituted on the aromatic nucleus, a     (C₁-C₆)alkyl-O—(C₁-C₁₀)alkyl radical and a     (C₃-C₆)cycloalkyl(C₁-C₁₀)alkyl radical; -   R³ and R⁴ each represent a (C₁-C₆)alkyl radical, or alternatively R³     represents a hydrogen atom and R⁴ represents a (C₁-C₁₀)alkyl     radical, or alternatively R³ and R⁴ form, together with the nitrogen     atom that bears them, a 5- or 6-membered heterocycle; -   R⁵, R⁶, R⁷ and R⁸ each represent a hydrogen atom; and -   R⁹ and R¹⁰, which are identical, each represent a hydrogen atom or a     methyl radical.

Among the possible substituents (radicals G) for the various radicals R¹ to R¹⁰ of the compounds of the formula (I), the following radicals or groups are preferred:

trifluoromethyl; halogen atom; amino; nitro; cyano; (C₁-C₁₀)alkyl radical; (C₂-C₆)alkynyl radical; (C₁-C₁₀)alkylcarbonyl radical; (C₃-C₁₀)cycloalkyl radical; trifluoromethoxy radical; di(C₁-C₁₀)alkylamino radical; (C₁-C₁₀)alkoxy-(C₁-C₁₀)alkyl radical; (C₁-C₁₀)alkoxy radical; (C₆-C₁₈)aryl radical optionally substituted by one or more radicals T; (C₆-C₁₈)aryloxy-(CO)_(n)— radical in which n is 0 or 1 and in which aryl is optionally substituted by one or more radicals T; (C₆-C₁₈)arylthio radical in which aryl is optionally substituted by one or more radicals T; saturated or unsaturated, monocyclic 5- to 8-membered heterocycle comprising one or more hetero atoms chosen from O, N and S, optionally substituted by one or more radicals T; and (C₂-C₁₀)alkynyl radical.

More particularly, the preferred compounds of the formula (I) are those chosen from:

-   N-(3-Amino-2,2-dimethylpropyl)-N′-(4-benzyloxyphenyl)-N″-(3-methylbutyl)guanidine     bis(trifluoroacetate); -   N-(3-Aminopropyl)-2-methyl-N′-[4-(2-methylbenzyloxy)phenyl]piperidine-1-carboxamidine     bis(trifluoroacetate); -   N-(3-Aminopropyl)-N′-(3-methylbutyl)-N″-(4-pentyloxyphenyl)guanidine     bis(trifluoroacetate); -   N-(3-Aminopropyl)-N′-[4-(2-methoxyethoxy)phenyl]-3-methylpiperidine-1-carboxamidine     bis(trifluoroacetate); -   N-(3-Aminopropyl)-N′-[4-(2-methoxyethoxy)phenyl]-4-methylpiperidine-1-carboxamidine     bis(trifluoroacetate); -   N′-(3-Aminopropyl)-N-ethyl-N-isopropyl-N″-[4-(2-methoxyethoxy)-phenyl]guanidine     bis(trifluoroacetate); -   N-(3-Aminopropyl)-4-methyl-N′-[4-(3-methylbutoxy)phenyl]piperidine-1-carboxamidine     bis(trifluoroacetate); -   N-(3-Aminopropyl)-2-methyl-N′-[4-(3-methylbutoxy)phenyl]piperidine-1-carboxamidine     bis(trifluoroacetate); -   N-(3-Aminopropyl)-2-ethyl-N′-[4-(3-methylbutoxy)phenyl]piperidine-1-carboxamidine     bis(trifluoroacetate); -   N′-(3-Aminopropyl)-N-ethyl-N-isopropyl-N″-[4-(3-methylbutoxy)phenyl]-guanidine     bis(trifluoroacetate); -   N-(3-Aminopropyl)-3-methyl-N′-(4-propoxyphenyl)piperidine-1-carboxamidine     bis(trifluoroacetate); -   N-(3-Aminopropyl)-4-methyl-N′-(4-propoxyphenyl)piperidine-1-carboxamidine     bis(trifluoroacetate); -   N-(3-Aminopropyl)-2-methyl-N′-(4-propoxyphenyl)piperidine-1-carboxamidine     bis(trifluoroacetate); -   N-(3-Aminopropyl)-2-ethyl-N′-(4-propoxyphenyl)piperidine-1-carboxamidine     bis(trifluoroacetate); -   N′-(3-Aminopropyl)-N-ethyl-N-isopropyl-N″-(4-propoxyphenyl)guanidine     bis(trifluoroacetate); -   N-(3-Aminopropyl)-N′-[4-(4-tert-butylbenzyloxy)phenyl]-2-methylpiperidine-1-carboxamidine     bis(trifluoroacetate); -   N-(3-Aminopropyl)-N′-[4-(4-tert-butylbenzyloxy)phenyl]-2-ethylpiperidine-1-carboxamidine     bis(trifluoroacetate); -   N-(3-Aminopropyl)-4-benzyl-N′-[4-(4,4,4-trifluorobutoxy)phenyl]piperidine-1-carboxamidine     bis(trifluoroacetate); -   N-(3-Aminopropyl)-2-ethyl-N′-(4-pentyloxyphenyl)piperidine-1-carboxamidine     bis(trifluoroacetate); and -   N′-(3-Amino-2,2-dimethylpropyl)-N-ethyl-N-isopropyl-N″-[4-(2-methylbenzyloxy)phenyl]guanidine     bis(trifluoroacetate).

The invention also relates to pharmaceutical compositions comprising a pharmaceutically effective amount of at least one compound of the formula (I) as defined above in combination with one or more pharmaceutically acceptable vehicles.

These compositions can be administered orally in the form of tablets, gel capsules or granules with immediate release or controlled release, intravenously in the form of an injectable solution, transdermally in the form of an adhesive transdermal device, or locally in the form of a solution, cream or gel.

A solid composition for oral administration is prepared by adding to the active principle a filler and, where appropriate, a binder, a disintegrating agent, a lubricant, a colorant or a flavour enhancer, and by forming the mixture into a tablet, a coated tablet, a granule, a powder or a capsule.

Examples of fillers include lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose and silicon dioxide, and examples of binders include poly(vinyl alcohol), poly(vinyl ether), ethylcellulose, methylcellulose, acacia, gum tragacanth, gelatine, shellac, hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate, dextrin and pectin. Examples of lubricants include magnesium stearate, talc, polyethylene glycol, silica and hardened plant oils. The colorant may be any of those permitted for used in medicaments. Examples of flavour enhancers include cocoa powder, mint in herb form, aromatic powder, mint in oil form, borneol and cinnamon powder. Obviously, the tablet or granule can be suitably coated with sugar, gelatine or the like.

An injectable form comprising the compound of the present invention as active principle is prepared, where appropriate, by mixing the said compound with a pH regulator, a buffer agent, a suspension agent, a solubiliser, a stabiliser, an isotonic agent and/or a preserving agent, and by converting the mixture into a form for intravenous, subcutaneous or intramuscular injection, according to a standard process. Where appropriate, the injectable form obtained can be freeze-dried via a standard process.

Examples of suspension agents include methylcellulose, polysorbate 80, hydroxyethylcellulose, acacia, powdered gum tragacanth, sodium carboxymethylcellulose and polyethoxylated sorbitan monolaurate.

Examples of solubilisers include castor oil solidified with polyoxyethylene, polysorbate 80, nicotinamide, polyethoxylated sorbitan monolaurate and the ethyl ester of castor oil fatty acid.

In addition, possible stabilisers include sodium sulfite, sodium metasulfite and ether, while possible preserving agents include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, phenol, cresol and chlorocresol.

The present invention also relates to the use of a compound of the formula (I) of the invention for the preparation of a medicament for the prevention or treatment of dyslipidaemia, atherosclerosis, type II diabetes and related diseases.

The effective administration doses and posologies of the compounds of the invention, intended for the prevention or treatment of a disease, disorder or condition caused by or associated with modulation of CETP activity, depends on a large number of factors, for example on the nature of the inhibitor, the size of the patient, the aim of the desired treatment, the nature of the pathology to be treated, the specific pharmaceutical composition used and the observations and conclusions of the treating physician.

For example, in the case of an oral administration, for example a tablet or a gel capsule, a possible suitable dosage of the compounds of the formula (I) is between about 0.1 mg/kg and about 100 mg/kg of body weight per day, preferably between about 0.5 mg/kg and about 50 mg/kg of body weight per day, more preferably between about 1 mg/kg and about 10 mg/kg of body weight per day and more preferably between about 2 mg/kg and about 5 mg/kg of body weight per day of active material.

If representative body weights of 10 kg and 100 kg are considered in order to illustrate the oral daily dosage range that can be used and as described above, suitable dosages of the compounds of the formula (I) will be between about 1-10 mg and 1000-10 000 mg per day, preferably between about 5-50 mg and 500-5000 mg per day, more preferably between about 10.0-100.0 mg and 100.0-1000.0 mg per day and even more preferably between about 20.0-200.0 mg and about 50.0-500.0 mg per day of active material comprising a preferred compound.

These dosage ranges represent total amounts of active material per day for a given patient. The number of administrations per day at which a dose is administered can vary within wide proportions depending on pharmacokinetic and pharmacological factors, such as the half-life of the active material, which reflects its rate of catabolism and clearance, and also the minimum and optimum levels of the said active material, in blood plasma or in other bodily fluids, which are reached in the patient and which are required for therapeutic efficacy.

Many other factors should also be taken into consideration when determining the number of daily administrations and the amount of active material that should be administered in a single dosage intake. Among these other factors, and not the least of which, is the individual response of the patient to be treated.

The present invention also relates to a general process for the preparation of the compounds of the formula (I) according to the synthetic scheme 1 presented in FIG. 1, in which the various variable substituents are as defined above for the compounds of the formula (I).

According to this process, the aryl thiocyanate (V) is subjected to the action of an amine HNR³R⁴, in a polar protic solvent medium, such as an alcohol, for example ethanol, to give, after heating, for example at the reflux point of the solvent, the corresponding thiourea. This thiourea is then placed in a reducing medium, for example in MnO₄ ⁻ medium, with the amine of the formula (III), to give the compound of the formula (I), which is isolated and purified, where appropriate.

This process (synthetic route 1) is particularly suitable for the synthesis of the compounds of the formula (I) for which R⁵, R⁶, R⁷ and R⁸ each represent a hydrogen atom.

According to one variant, the compounds of the formula (I) according to the present invention can also be prepared according to a process involving synthesis on a support, especially on resin.

This process is illustrated by scheme 2, presented in FIG. 2, in which scheme:

-   the compound of the formula (II), in which:     represents a graft on resin, for example of Bromo Wang type; —X is     chosen from a hydrogen atom, a halogen atom, a (C₁-C₆)alkyl radical     and a (C₁-C₆)alkoxy radical;     -   is placed in contact with an excess of the amine of the         formula (III) in an apolar aprotic solvent, for example         dichloromethane, generally at room temperature, to give the         compound of the formula (IV); -   the compound of the formula (IV) is then reacted, under conditions     similar to those described above, with a compound of the formula     (V), to give the thiourea of the formula (VI); -   the said thiourea (VI) is converted, by the action of an amine of     the formula (VII), generally at room temperature, in a polar aprotic     medium, for example DMF, and in the presence of mercuric salts, for     example HgCl₂, to give the guanidine of the formula (VIII); -   the guanidine (VIII) is then detached from the resin, according to     any technique known per se, for example using trifluoroacetic acid,     dichloromethane and triisopropylsilane, to give the compounds of the     formula (I_(A)), which are a special case of the compounds of the     formula (I) for which R⁹ and R¹⁰ each represent a hydrogen atom; -   and the terminal amine of these compounds of the formula (I_(A)) can     optionally be selectively mono- or dialkylated according to standard     amine alkylation techniques that are well known to those skilled in     the art.

In the processes described above, it should be understood that the operating conditions can vary substantially depending on the various substituents present in the compounds of the formula (I) that it is desired to prepare. Such variations and adaptations are readily accessible to a person skilled in the art, for example from scientific reviews, the patent literature, Chemical Abstracts, and computer databases, including the Internet Similarly, the starting materials are either commercially available or are accessible via syntheses that a person skilled in the art can readily find, for example in the various publications and databases described above.

By way of example of a variant of the process described above, the compounds of the general formula (I), for which R⁵, R⁶, R⁷ and R⁸ each represent a hydrogen atom, can advantageously be prepared according to the synthetic scheme 3 presented in FIG. 3.

The possible optical isomers of the compounds of the formula (I) can be obtained on the one hand via standard techniques for separating and/or purifying isomers known to those skilled in the art, from the racemic mixture of the compound of the formula (I). The optical isomers can also be obtained directly via stereoselective synthesis of an optically active starting compound.

The examples that follow illustrate the present invention without limiting it in any way. In these examples and in the proton nuclear magnetic resonance data (300 MHz NMR), the following abbreviations have been used: s for singlet, d for doublet, t for triplet, q for quartet, o for octet, m for complex multiplet and b for broad. The chemical shifts δ are expressed in ppm, unless otherwise indicated. TFA means trifluoroacetic acid.

EXAMPLES Example 1 N-(4-benzyloxyphenyl)-N′-(3-dimethylamino-2,2-dimethylpropyl)-N″-(3-methylbutyl)guanidine

(Synthetic Scheme 1)

Step a): N-(4-benzyloxyphenyl)-N′-(3-methylbutyl)thiourea

A suspension of 4-benzyloxyphenyl isothiocyanate (2 g) in ethanol (10 ml) is maintained at reflux until dissolution is complete. 3-Methylbutylamine (0.72 g; 1 eq.) is then added in a single portion. The reaction medium is refluxed for 3 hours. After cooling, the mixture is taken up in water and the white precipitate is then filtered off by suction and dried. After purification by chromatography on silica (eluent: dichloromethane), 2 g of N-(4-benzyloxyphenyl)-N′-(3-methylbutyl)thiourea are obtained.

¹H NMR (300 MHz, CDCl₃) δ: 0.83 ppm (6 H, d, J=6.6 Hz); 1.34 ppm (2 H, m); 1.50 ppm (1 H, m); 3.54 ppm (2 H, m); 5.00 ppm (2 H, s); 5.70 ppm (1 H, bs); 6.94 ppm (2 H, d, J=9.0 Hz); 7.06 ppm (2 H, d, J=9.0 Hz); 7.33 ppm (5 H, m); 7.48 ppm (1 H, bs).

Step b): N-(4-benzyloxyphenyl)-N′-(3-dimethylamino-2,2-dimethylpropyl)-N″-(3-methylbutyl)guanidine

Benzyltriethylammonium permanganate (0.281 g; 1.5 eq.) is added, at 5° C. and portionwise, to a solution of N-(4-benzyloxyphenyl)-N′-(3-methylbutyl)thiourea (0.200 g) and 3-dimethylamino-2,2-dimethylpropylamine (0.156 g; 2 eq.) in tetrahydrofuran (THF; 2.2 ml). The reaction medium is stirred for three days at room temperature. After filtration and concentration, the product is purified by chromatography on silica (eluent: methanol +0.1% acetic acid). The product, dissolved in dichloromethane, is washed with 1N sodium hydroxide. After drying and concentration, 0.067 g of N-(4-benzyloxyphenyl)-N′-(3-dimethylamino-2,2-dimethylpropyl)-N″-(3-methylbutyl)guanidine is obtained.

MS: 425.4 (M+H⁺)

¹H NMR (300 MHz, CDCl₃) δ: 0.84 ppm (12 H, m); 1.33 ppm (4 H, m); 1.52 ppm (4 H, bm); 2.18 ppm (6 H, m); 3.03 ppm (3 H, bm); 4.95 ppm (2 H, s); 6.75 ppm (2 H, d, J=9.0 Hz); 6.82 ppm (2 H, d, J=9.0 Hz); 7.33 ppm (5 H, m).

Examples A General Procedure for the Preparation of the N′-(3-aminopropyl)-N″-(benzyloxyphenyl)-N,N-dialkylguanidine compounds

(Synthetic Scheme 2)

Step a): General Procedure for the Preparation of the 1,3-propanediamine Resins

2-Chlorotrityl chloride resin (25 g, 1 eq.) is added, in four portions at intervals of one hour, to a solution of 1,3-propanediamine (147 g, 50 eq.) in dichloromethane (1 I). After stirring for a further one hour at room temperature, methanol (500 ml) is added and stirring is continued for 20 minutes. The resin is filtered off and then washed with methanol (3×350 ml), a ¼ TEA/DMF (triethanolamine/dimethylformamide) mixture, methanol (MeOH; 3×350 ml) and dichloromethane (3×350 ml). The resin is then dried under vacuum,

Step b): General Procedure for the Preparation of the N-(3-aminopropyl)-N′-(benzyloxyphenyl)thiourea Resins

A 0.24 M solution of benzyloxyphenyl isothiocyanate in dichloromethane (4.5 ml; 6 eq.) is added to a reactor containing the 1,3-propanediamine resin (180 μmol; 1 eq.). The suspension is stirred for 4 hours at room temperature. The resin is then washed with dichloromethane (3×5 ml) and N-methylpyrrolidone (NMP; 3×5 ml). The resin is stored as a suspension in NMP (1 ml) and then used in the following reaction.

Step c): General Procedure for the Preparation of the N′-(3-aminopropyl)-N″-(benzyloxyphenyl)-N,N-dialkylguanidine Resins

The suspension of N-(3-aminopropyl)-N′-(benzyloxyphenyl)thiourea resin in dimethylformamide (DMF; 1 ml) is treated with a 0.72 M solution of amine in DMF (1 ml; 6 eq.) and with a 0.72 M solution of mercuric chloride in DMF (1 ml; 6 eq.). The reaction is stirred for 8 hours at 25° C. The resin is then washed with a thiocarbamate solution in a mixture of THF/water solvents (2×5 ml), with DMF (3×5 ml), methanol (3×5 ml) and dichloromethane (3×5 ml). The resin, stored as a suspension in dichloromethane (1 ml), is then used in the following reaction.

Step d): General Procedure for the Preparation of the N′-(3-aminopropyl)-N″-(benzyloxyphenyl)-N,N-dialkylguanidine Compounds

The suspension of N′-(3-aminopropyl)-N″-(benzyloxyphenyl)-N,N-dialkylguanidine resin in dichloromethane (1 ml) is treated with a solution of 40% trifluoroacetic acid (TFA) and 10% triisopropylsilane in dichloromethane (1 ml). The reaction is stirred for 1 hour at room temperature and is then filtered and the filtrate is concentrated in a centrifuge under vacuum to give the compound N′-(3-aminopropyl)-N″-(benzyloxyphenyl)-N,N-dialkylguanidine in the form of the di-TFA salt.

The compounds of Examples 2-16 below were obtained according to the procedure described above.

Example 2 N-(3-Amino-2,2-dimethylpropyl)-N′-(3-benzyloxyphenyl)-N″-(3-methylbutyl)-guanidine

Salt: TFA×2

Mass: ES+ 397.5

Example 3 N-(3-Amino-2,2-dimethylpropyl)-N′-(4-benzyloxyphenyl)-3-hydroxymethylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 425.5

Example 4 N-(3-Amino-2,2-dimethylpropyl)-N′-(4-benzyloxyphenyl)pyrrolidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 381.5

Example 5 N-(3-Amino-2,2-dimethylpropyl)-N′-(4-benzyloxyphenyl)-N″-(3-methylbutyl)-guanidine

Salt: TFA×2

Mass: ES+ 397.5

Example 6 N-(3-Aminopropyl)-N′-(3-benzyloxyphenyl)pyrrolidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 353.4

Example 7 N-(3-Aminopropyl)-N′-(4-benzyloxyphenyl)-N″-phenethylguanidine

Salt: TFA×2

Mass: ES+ 403.5

Example 8 N-(3-Aminopropyl)-N ′-(3-benzyloxyphenyl)-N″-(3-methylbutyl)guanidine

Salt: TFA×2

Mass: ES+ 369.3

Example 9 N-(3-Aminopropyl)-N′-(3-benzyloxyphenyl)-3-hydroxymethylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 397.3

Example 10 N-(3-Aminopropyl)-N′-(4-benzyloxyphenyl)pyrrolidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 353.3

Example 11 N-(3-Aminopropyl)-N′-(4-benzyloxyphenyl)-3-hydroxymethylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 397.3

Example 12 N-(3-Aminopropyl)-N′-(4-benzyloxyphenyl)-N″-(3-methylbutyl)guanidine

Salt: TFA×2

Mass: ES+ 369.3

Example 13 N-(3-Amino-2,2-dimethylpropyl)-N′-(3-benzyloxyphenyl)-3-hydroxymethylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 425.4

Example 14 N-(3-Amino-2,2-dimethylpropyl)-N′-(3-benzyloxyphenyl)pyrrolidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 381.4

Example 15 N-(3-Aminopropyl)-N′-(4-benzyloxyphenyl)-2-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 381.4

Example 16 N-(3-Aminopropyl)-N′-(3-benzyloxyphenyl)-2-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 381.4

Examples B General Procedure for the Preparation of the N′-(3-aminopropyl)-N″-(benzyloxyphenyl)-N,N-dialkylguanidine compounds

(Synthetic Scheme 3)

Step a): General Procedure for the Preparation of the N-(3-aminopropyl)-N′-(4-hydroxyphenyl)thiourea Resins

A 0.24 M solution of hydroxyphenyl isothiocyanate in dichloromethane (4.5 ml; 6 eq.) is added to a reactor containing the diaminoalkyl resin (180 μmol; 1 eq.). The suspension is stirred for 4 hours at room temperature. The resin is then washed with dichloromethane (3×5 ml) and NMP (3×5 ml). The resin, stored as a suspension in NMP (1 ml), is then used in the following reaction.

Step b): General Procedure for the Preparation of the N-(3-aminopropyl)-N′-(4-alkoxyphenyl)-S-alkylisothiourea Resins

The suspension of N-(3-aminopropyl)-N′-(4-hydroxyphenyl)thiourea resin in NMP (1 ml) is treated with a 0.48 M solution of phosphazene base tBuP1 in NMP (1.5 ml; 4 eq.) and with a 0.72 M solution of alkyl halide in NMP (1.5 ml; 6 eq.). The reaction is stirred for 2 hours at 50° C. The resin is then washed with methanol (3×5 ml), THF (3×5 ml), dichloromethane (3×5 ml) and DMF (3×5 ml). The resin, stored as a suspension in DMF (1 ml), is then used in the following reaction.

Step c): General Procedure for the Preparation of the N′-(3-aminopropyl)-N″-(4-alkoxyphenyl)-N,N-dialkylguanidine Resins

The suspension of N-(3-aminopropyl)-N′-(4-alkoxyphenyl)-S-alkylisothiourea resin in DMF (1 ml) is treated with a 0.39 M solution of amine in DMF (1.4 ml; 3 eq.) and with a 0.36 M solution of mercuric chloride in DMF (1.5 ml; 3 eq.). The reaction is stirred for 16 hours at 50° C. The resin is then washed with a solution of thiocarbamate in a mixture of THF/water solvents (2×5 ml), with DMF (3×5 ml), methanol (3×5 ml) and dichloromethane (3×5 ml). The resin, stored as a suspension in dichloromethane (1 ml), is then used in the following reaction.

Step d): General Procedure for the Preparation of the N′-(3-aminopropyl)-N″-(4-alkoxyphenyl)-N,N-dialkylguanidine Compounds

The suspension of N′-(3-aminopropyl)-N″-(4-alkoxyphenyl)-N,N-dialkylguanidine resin in dichloromethane (1 ml) is treated with a 20% solution of TFA in dichloromethane (1 ml). The reaction is stirred for 1 hour at room temperature. The reaction is then filtered and the filtrate is concentrated in a centrifuge under vacuum to give the N′-(3-aminopropyl)-N″-(4-alkoxyphenyl)-N,N-dialkylguanidine compound in the form of the di-TFA salt.

The compounds of Examples 17-198 below were obtained according to the procedure described above.

Example 17 N-(3-Aminopropyl)-2-methyl-N′-[4-(4-trifluoromethylbenzyloxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 449.4

Example 18 N-(3-Aminopropyl)-2-methyl-N′-[4-(2-methylbenzyloxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 395.5

Example 19 N-(3-Aminopropyl)-2-methyl-N′-(4-pentyloxyphenyl)piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 361.4

Example 20 N-(3-Aminopropyl)-N′-(3-methylbutyl)-N″-(4-pentyloxyphenyl)guanidine

Salt: TFA×2

Mass: ES+ 349.4

Example 21 N-(3-Aminopropyl)-N′-[4-(2-methylbenzyloxy)phenyl]-N″-(3-methylbutyl)guanidine

Salt: TFA×2

Mass: ES+ 383.3

Example 22 N-(3-Aminopropyl)-N′-(3-methylbutyl)-N″-[4-(4-trifluoromethylbenzyloxy)-phenyl]guanidine

Salt: TFA×2

Mass: ES+ 437.4

Example 23 N-(3-Aminopropyl)-4-benzyl-N′-[4-(4-methylbenzyloxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 471.3

Example 24 N-(3-Aminopropyl)-3-methyl-N′-[4-(4-methylbenzyloxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 395.3

Example 25 N-(3-Aminopropyl)-4-methyl-N′-[4-(4-methylbenzyloxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 395.4

Example 26 N-(3-Aminopropyl)-2-methyl-N′-[4-(4-methylbenzyloxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 395.4

Example 27 N-(3-Aminopropyl)-2-ethyl-N′-[4-(4-methylbenzyloxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 409.4

Example 28 N′-(3-Aminopropyl)-N-ethyl-N-isopropyl-N″-[4-(4-methylbenzyloxy)phenyl]-guanidine

Salt: TFA×2

Mass: ES+ 383.4

Example 29 N-(3-Aminopropyl)-4-benzyl-N′-[4-(2-methoxyethoxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 425.4

Example 30 N-(3-Aminopropyl)-N′-[4-(2-methoxyethoxy)phenyl]-3-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 349.3

Example 31 N-(3-Aminopropyl)-N′-[4-(2-methoxyethoxy)phenyl]-4-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 349.3

Example 32 N′-(3-Aminopropyl)-N-ethyl-N-isopropyl-N″-[4-(2-methoxyethoxy)phenyl]guanidine

Salt: TFA×2

Mass: ES+ 337.3

Example 33 N-(3-Aminopropyl)-2-methyl-N′-[4-(3-methylbut-2-enyloxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 359.4

Example 34 N′-(3-Aminopropyl)-N-ethyl-N-isopropyl-N″-[4-(3-methylbut-2-enyloxy)phenyl]-guanidine

Salt: TFA×2

Mass: ES+ 347.4

Example 35 N-(3-Aminopropyl)-4-benzyl-N′-[4-(3-methylbutoxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 437.4

Example 36 N-(3-Aminopropyl)-4-methyl-N′-[4-(3-methylbutoxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 361.4

Example 37 N-(3-Aminopropyl)-2-methyl-N′-[4-(3-methylbutoxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 361.4

Example 38 N-(3-Aminopropyl)-2-ethyl-N′-[4-(3-methylbutoxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 375.4

Example 39 N′-(3-Aminopropyl)-N-ethyl-N-isopropyl-N″-[4-(3-methylbutoxy)phenyl]guanidine

Salt: TFA×2

Mass: ES+ 349.4

Example 40 N-(3-Aminopropyl)-4-benzyl-N′-(4-decyloxyphenyl)piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 507.5

Example 41 N-(3-Aminopropyl)-N′-(4-decyloxyphenyl)-3-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 431.4

Example 42 N-(3-Aminopropyl)-N′-(4-decyloxyphenyl)-4-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 431.5

Example 43 N-(3-Aminopropyl)-N′-(4-decyloxyphenyl)-2-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 431.4

Example 44 N-(3-Aminopropyl)-N′-(4-decyloxyphenyl)-2-ethylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 445.5

Example 45 N′-(3-Aminopropyl)-N″-(4-decyloxyphenyl)-N-ethyl-N-isopropylguanidine

Salt: TFA×2

Mass: ES+ 419.5

Example 46 N-(3-Aminopropyl)-4-benzyl-N′-(4-propoxyphenyl)piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 409.4

Example 47 N-(3-Aminopropyl)-3-methyl-N′-(4-propoxyphenyl)piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 333.3

Example 48 N-(3-Aminopropyl)-4-methyl-N′-(4-propoxyphenyl)piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 333.3

Example 49 N-(3-Aminopropyl)-2-methyl-N′-(4-propoxyphenyl)piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 333.3

Example 50 N-(3-Aminopropyl)-2-ethyl-N′-(4-propoxyphenyl)piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 347.4

Example 51 N′-(3-Aminopropyl)-N-ethyl-N-isopropyl-N″-(4-propoxyphenyl)guanidine

Salt: TFA×2

Mass: ES+ 321.4

Example 52 N-(3-Aminopropyl)-4-benzyl-N′-[4-(5-methylhexyloxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 465.4

Example 53 N-(3-Aminopropyl)-3-methyl-N′-[4-(5-methylhexyloxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 389.4

Example 54 N-(3-Aminopropyl)-4-methyl-N′-[4-(5-methylhexyloxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 389.4

Example 55 N-(3-Aminopropyl)-2-methyl-N′-[4-(5-methylhexyloxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 389.4

Example 56 N-(3-Aminopropyl)-2-ethyl-N′-[4-(5-methylhexyloxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 403.4

Example 57 N′-(3-Aminopropyl)-N-ethyl-N-isopropyl-N″-[4-(5-methylhexyloxy)phenyl]guanidine

Salt: TFA×2

Mass: ES+ 377.4

Example 58 N-(3-Aminopropyl)-N′-[4-(4-tert-butylbenzyloxy)phenyl]-3-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 437.4

Example 59 N-(3-Aminopropyl)-N′-[4-(4-tert-butylbenzyloxy)phenyl]-4-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 437.4

Example 60 N-(3-Aminopropyl)-N′-[4-(4-tert-butylbenzyloxy)phenyl]-2-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 437.4

Example 61 N-(3-Aminopropyl)-N′-[4-(4-tert-butylbenzyloxy)phenyl]-2-ethylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 451.4

Example 62 N-(3-Aminopropyl)-4-benzyl-N′-[4-(4-cyanobenzyloxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 482.3

Example 63 N-(3-Aminopropyl)-N′-[4-(4-cyanobenzyloxy)phenyl]-3-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 406.3

Example 64 N-(3-Aminopropyl)-N′-[4-(4-cyanobenzyloxy)phenyl]-4-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 406.3

Example 65 N-(3-Aminopropyl)-N′-[4-(4-cyanobenzyloxy)phenyl]-2-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 406.3

Example 66 N-(3-Aminopropyl)-N′-[4-(4-cyanobenzyloxy)phenyl]-2-ethylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 420.4

Example 67 N′-(3-Aminopropyl)-N″-[4-(4-cyanobenzyloxy)phenyl]-N-ethyl-N-isopropyl-guanidine

Salt: TFA×2

Mass: ES+ 394.3

Example 68 N-(3-Aminopropyl)-4-benzyl-N′-[4-(2-cyanobenzyloxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 482.3

Example 69 N-(3-Aminopropyl)-N′-[4-(2-cyanobenzyloxy)phenyl]-3-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 406.3

Example 70 N-(3-Aminopropyl)-N′-[4-(2-cyanobenzyloxy)phenyl]-4-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 406.3

Example 71 N-(3-Aminopropyl)-N′-[4-(2-cyanobenzyloxy)phenyl]-2-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 406.3

Example 72 N-(3-Aminopropyl)-N′-[4-(2-cyanobenzyloxy)phenyl]-2-ethylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 420.3

Example 73 N-(3-Aminopropyl)-N′-[4-(2-cyclohexylethoxy)phenyl]-3-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 401.4

Example 74 N-(3-Aminopropyl)-N′-[4-(2-cyclohexylethoxy)phenyl]-4-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 401.4

Example 75 N-(3-Aminopropyl)-N′-[4-(2-cyclohexylethoxy)phenyl]-2-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 401.4

Example 76 N-(3-Aminopropyl)-N′-[4-(2-cyclohexylethoxy)phenyl]-2-ethylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 415.4

Example 77 N′-(3-Aminopropyl)-N″-[4-(2-cyclohexylethoxy)phenyl]-N-ethyl-N-isopropyl-guanidine

Salt: TFA×2

Mass: ES+ 389.4

Example 78 N-(3-Aminopropyl)-4-benzyl-N′-[4-(3-cyanopropoxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 434.3

Example 79 N-(3-Aminopropyl)-N′-[4-(3-cyanopropoxy)phenyl]-3-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 358.3

Example 80 N-(3-Aminopropyl)-N′-[4-(3-cyanopropoxy)phenyl]-4-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 358.2

Example 81 N-(3-Aminopropyl)-N′-[4-(3-cyanopropoxy)phenyl]-2-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 358.2

Example 82 N-(3-Aminopropyl)-N′-[4-(3-cyanopropoxy)phenyl]-2-ethylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 372.3

Example 83 N′-(3-Aminopropyl)-N″-[4-(3-cyanopropoxy)phenyl]-N ethyl-N-isopropyl-guanidine

Salt: TFA×2

Mass: ES+ 346.3

Example 84 N-(3-Aminopropyl)-4-benzyl-N′-[4-(2-methylbenzyloxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 471.4

Example 85 N-(3-Aminopropyl)-3-methyl-N′-[4-(2-methylbenzyloxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 395.4

Example 86 N-(3-Aminopropyl)-4-methyl-N′-[4-(2-methylbenzyloxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 395.3

Example 87 N-(3-Aminopropyl)-2-ethyl-N′-[4-(2-methylbenzyloxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 409.4

Example 88 N′-(3-Aminopropyl)-N-ethyl-N-isopropyl-N″-[4-(2-methylbenzyloxy)phenyl]-guanidine

Salt: TFA×2

Mass: ES+ 383.4

Example 89 N-(3-Aminopropyl)-4-benzyl-N′-[4-(3-trifluoromethoxybenzyloxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 541.3

Example 90 N-(3-Aminopropyl)-3-methyl-N′-[4-(3-trifluoromethoxybenzyloxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 465.3

Example 91 N-(3-Aminopropyl)-4-methyl-N′-[4-(3-trifluoromethoxybenzyloxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 465.3

Example 92 N-(3-Aminopropyl)-2-methyl-N′-[4-(3-trifluoromethoxybenzyloxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 465.3

Example 93 N-(3-Aminopropyl)-2-ethyl-N′-[4-(3-trifluoromethoxybenzyloxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 479.3

Example 94 N′-(3-Aminopropyl)-N-ethyl-N-isopropyl-N″-[4-(3-trifluoromethoxybenzyloxy)-phenyl]guanidine

Salt: TFA×2

Mass: ES+ 453.3

Example 95 N-(3-Aminopropyl)-4-benzyl-N′-[4-(4,4,4-trifluorobutoxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 477.3

Example 96 N-(3-Aminopropyl)-3-methyl-N′-[4-(4,4,4-trifluorobutoxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 401.3

Example 97 N-(3-Aminopropyl)-4-methyl-N′-[4-(4,4,4-trifluorobutoxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 401.3

Example 98 N-(3-Aminopropyl)-2-methyl-N′-[4-(4,4,4-trifluorobutoxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 401.3

Example 99 N-(3-Aminopropyl)-2-ethyl-N′-[4-(4,4,4-trifluorobutoxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 415.3

Example 100 N′-(3-Aminopropyl)-N-ethyl-N-isopropyl-N″-[4-(4,4,4-trifluorobutoxy)phenyl]-guanidine

Salt: TFA×2

Mass: ES+ 389.3

Example 101 N-(3-Aminopropyl)-4-benzyl-N′-(4-pentyloxyphenyl)piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 437.4

Example 102 N-(3-Aminopropyl)-3-methyl-N′-(4-pentyloxyphenyl)piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 361.4

Example 103 N-(3-Aminopropyl)-4-methyl-N′-(4-pentyloxyphenyl)piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 361.4

Example 104 N-(3-Aminopropyl)-2-ethyl-N′-(4-pentyloxyphenyl)piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 375.4

Example 105 N′-(3-Aminopropyl)-N-ethyl-N-isopropyl-N″-(4-pentyloxyphenyl)guanidine

Salt: TFA×2

Mass: ES+ 349.4

Example 106 N-(3-Aminopropyl)-4-benzyl-N′-[4-(4-methanesulfonylbenzyloxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 535.3

Example 107 N-(3-Aminopropyl)-N′-[4-(4-methanesulfonylbenzyloxy)phenyl]-3-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 459.3

Example 108 N-(3-Aminopropyl)-N′-[4-(4-methanesulfonylbenzyloxy)phenyl]-4-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 459.3

Example 109 N-(3-Aminopropyl)-N′-[4-(4-methanesulfonylbenzyloxy)phenyl]-2-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 459.3

Example 110 N-(3-Aminopropyl)-2-ethyl-N′-[4-(4-methanesulfonylbenzyloxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 473.3

Example 111 N′-(3-Aminopropyl)-N-ethyl-N-isopropyl-N″-[4-(4-methanesulfonylbenzyloxy)-phenyl]guanidine

Salt: TFA×2

Mass: ES+ 447.3

Example 112 N-(3-Aminopropyl)-4-benzyl-N′-[4-(4-trifluoromethoxybenzyloxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 541.3

Example 113 N-(3-Aminopropyl)-3-methyl-N′-[4-(4-trifluoromethoxybenzyloxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 465.3

Example 114 N-(3-Aminopropyl)-4-methyl-N′-[4-(4-trifluoromethoxybenzyloxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 465.3

Example 115 N-(3-Aminopropyl)-2-methyl-N′-[4-(4-trifluoromethoxybenzyloxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 465.3

Example 116 N-(3-Aminopropyl)-2-ethyl-N′-[4-(4-trifluoromethoxybenzyloxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 479.3

Example 117 N′-(3-Aminopropyl)-N-ethyl-N-isopropyl-N″-[4-(4-trifluoromethoxybenzyloxy)-phenyl]guanidine

Salt: TFA×2

Mass: ES+ 453.3

Example 118 N-(3-Amino-2,2-dimethylpropyl)-4-benzyl-N′-[4-(4-methylbenzyloxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 499.3

Example 119 N-(3-Amino-2,2-dimethylpropyl)-3-methyl-N′-[4-(4-methylbenzyloxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 423.3

Example 120 N-(3-Amino-2,2-dimethylpropyl)-4-methyl-N′-[4-(4-methylbenzyloxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 423.3

Example 121 N-(3-Amino-2,2-dimethylpropyl)-2-methyl-N′-[4-(4-methylbenzyloxy)phenyl-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 423.3

Example 122 N-(3-Amino-2,2-dimethylpropyl)-2-ethyl-N′-[4-(4-methylbenzyloxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 437,3

Example 123 N′-(3-Amino-2,2-dimethylpropyl)-N-ethyl-N-isopropyl-N″-[4-(4-methylbenzyloxy)phenyl]guanidine

Salt: TFA×2

Mass: ES+ 411.3

Example 124 N-(3-Amino-2,2-dimethylpropyl)-N′-[4-(2-methoxyethoxy)phenyl]-3-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 377.3

Example 125 N-(3-Amino-2,2-dimethylpropyl)-N′-[4-(2-methoxyethoxy)phenyl]-4-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 377.3

Example 126 N-(3-Amino-2,2-dimethylpropyl)-N′-[4-(2-methoxyethoxy)phenyl]-2-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 377.3

Example 127 N-(3-Amino-2,2-dimethylpropyl)-2-methyl-N′-[4-(3-methylbut-2-enyloxy)-phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 387.3

Example 128 N-(3-Amino-2,2-dimethylpropyl)-3-methyl-N′-[4-(3-methylbutoxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 389.4

Example 129 N-(3-Amino-2,2-dimethylpropyl)-4-methyl-N′-[4-(3-methylbutoxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 389.4

Example 130 N-(3-Amino-2,2-dimethylpropyl)-2-methyl-N′-[4-(3-methylbutoxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 389.4

Example 131 N-(3-Amino-2,2-dimethylpropyl)-2-ethyl-N′-[4-(3-methylbutoxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 403.4

Example 132 N′-(3-Amino-2,2-dimethylpropyl)-N-ethyl-N-isopropyl-N″-[4-(3-methylbutoxy)-phenyl]guanidine

Salt: TFA×2

Mass: ES+ 377.4

Example 133 N-(3-Amino-2,2-dimethylpropyl)-N′-(4-decyloxyphenyl)-3-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 459.4

Example 134 N-(3-Amino-2,2-dimethylpropyl)-N′-(4-decyloxyphenyl)-4-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 459.5

Example 135 N-(3-Amino-2,2-dimethylpropyl)-N′-(4-decyloxyphenyl)-2-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 459.5

Example 136 N-(3-Amino-2,2-dimethylpropyl)-N′-(4-decyloxyphenyl)-2-ethylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 473.5

Example 137 N′-(3-Amino-2,2-dimethylpropyl)-N″-(4-decyloxyphenyl)-N-ethyl-N-isopropyl-guanidine

Salt: TFA×2

Mass: ES+ 447.5

Example 138 N-(3-Amino-22-dimethylpropyl)-4-benzy-N′-(4-propoxyphenyl)piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 437.4

Example 139 N-(3-Amino-2,2-dimethylpropyl)-3-methyl-N′-(4-propoxyphenyl)piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 361.4

Example 140 N-(3-Amino-2,2-dimethylpropyl)-4-methyl-N′-(4-propoxyphenyl)piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 361.4

Example 141 N-(3-Amino-2,2-dimethylpropyl)-2-methyl-N′-(4-propoxyphenyl)piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 361.4

Example 142 N-(3-Amino-2,2-dimethylpropyl)-2-ethyl-N′-(4-propoxyphenyl)piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 375.4

Example 143 N′-(3-Amino-2,2-dimethylpropyl)-N-ethyl-N-isopropyl-N″-(4-propoxyphenyl)-guanidine

Salt: TFA×2

Mass: ES+ 349.4

Example 144 N-(3-Amino-2,2-dimethylpropyl)-4-benzyl-N′-[4-(5-methylhexyloxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 493.5

Example 145 N-(3-Amino-2,2-dimethylpropyl)-3-methyl-N′-[4-(5-methylhexyloxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 417.4

Example 146 N-(3-Amino-2,2-dimethylpropyl)-4-methyl-N′-[4-(5-methylhexyloxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 417.4

Example 147 N-(3-Amino-2,2-dimethylpropyl)-2-methyl-N′-[4-(5-methylhexyloxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 417.4

Example 148 N-(3-Amino-2,2-dimethylpropyl)-2-ethyl-N′-[4-(5-methylhexyloxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 431.4

Example 149 N′-(3-Amino-2,2-dimethylpropyl)-N-ethyl-N-isopropyl-N″-[4-(5-methylhexyloxy)phenyl]guanidine

Salt: TFA×2

Mass: ES+ 405.4

Example 150 N-(3-Amino-2,2-dimethylpropyl)-N′-[4-(4-tert-butylbenzyloxy)phenyl]-3-methylpiperidine-1-carboxamidine

Salt TFA×2

Mass: ES+ 465.4

Example 151 N-(3-Amino-2,2-dimethylpropyl)-N′-[4-(4-tert-butylbenzyloxy)phenyl]-4-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 465.4

Example 152 N-(3-Amino-2,2-dimethylpropyl)-N′-[4-(4-tert-butylbenzyloxy)phenyl]-2-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 465.4

Example 153 N-(3-Amino-2,2-dimethylpropyl)-N′-[4-(4-tert-butylbenzyloxy)phenyl]-2-ethyl-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 479.4

Example 154 N′-(3-Amino-2,2-dimethylpropyl)-N″-[4-(4-tert-butylbenzyloxy)phenyl]-N-ethyl-N-isopropylguanidine

Salt: TFA×2

Mass: ES+ 453.4

Example 155 N-(3-Amino-2,2-dimethylpropyl)-4-benzyl-N′-[4-(4-cyanobenzyloxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 510.4

Example 156 N-(3-Amino-2,2-dimethylpropyl)-N′-[4-(4-cyanobenzyloxy)phenyl]-3-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 434.4

Example 157 N-(3-Amino-2,2-dimethylpropyl)-N′-[4-(4-cyanobenzyloxy)phenyl]-4-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 434.4

Example 158 N-(3-Amino-2,2-dimethylpropyl)-N′-[4-(4-cyanobenzyloxy)phenyl]-2-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 434.4

Example 159 N′-(3-Amino-2,2-dimethylpropyl)-N″-[4-(4-cyanobenzyloxy)phenyl]-N-ethyl-N-isopropylguanidine

Salt: TFA×2

Mass: ES+ 422.4

Example 160 N-(3-Amino-2,2-dimethylpropyl)-N′-[4-(2-cyanobenzyloxy)phenyl]-3-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 434.4

Example 161 N-(3-Amino-2,2-dimethylpropyl)-N′-[4-(2-cyanobenzyloxy)phenyl]-2-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 434.4

Example 162 N′-(3-Amino-2,2-dimethylpropyl)-N″-[4-(2-cyanobenzyloxy)phenyl]-N-ethyl-N-isopropylguanidine

Salt: TFA×2

Mass: ES+ 422.4

Example 163 N-(3-Amino-2,2-dimethylpropyl)-4-benzyl-N′-[4-(2-cyclohexylethoxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 505.4

Example 164 N-(3-Amino-2,2-dimethylpropyl)-N′-4-(2-cyclohexylethoxy)phenyl]-3-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 429.4

Example 165 N-(3-Amino-2,2-dimethylpropyl)-N′-[4-(2-cyclohexylethoxy)phenyl]-4-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 429.4

Example 166 N-(3-Amino-2,2-dimethylpropyl)-N′-[4-(2-cyclohexylethoxy)phenyl]-2-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 429.4

Example 167 N-(3-Amino-2,2-dimethylpropyl)-N′-[4-(2-cyclohexylethoxy)phenyl]-2-ethylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 443.5

Example 168 N′-(3-Amino-2,2-dimethylpropyl)-N″-[4-(2-cyclohexylethoxy)phenyl]-N-ethyl-N-isopropylguanidine

Salt: TFA×2

Mass: ES+ 417.4

Example 169 N-(3-Amino-2,2-dimethylpropyl)-4-benzyl-N′-[4-(3-cyanopropoxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 462.4

Example 170 N-(3-Amino-2,2-dimethylpropyl)-N′-[4-(3-cyanopropoxy)phenyl]-3-methyl-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 386.4

Example 171 N-(3-Amino-2,2-dimethylpropyl)-N′-[4-(3-cyanopropoxy)phenyl]-4-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 386.4

Example 172 N-(3-Amino-2,2-dimethylpropyl)-N′-[4-(3-cyanopropoxy)phenyl]-2-ethylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 400.4

Example 173 N-(3-Amino-2,2-dimethylpropyl)-4-benzyl-N′-[4-(2-methylbenzyloxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 499.4

Example 174 N-(3-Amino-2,2-dimethylpropyl)-3-methyl-N′-[4-(2-methylbenzyloxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 423.4

Example 175 N-(3-Amino-2,2-dimethylpropyl)-2-methyl-N′-[4-(2-methylbenzyloxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 423.4

Example 176 N-(3-Amino-2,2-dimethylpropyl)-2-ethyl-N′-[4-(2-methylbenzyloxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 437.4

Example 177 N′-(3-Amino-2,2-dimethylpropyl)-N-ethyl-N-isopropyl-N″-[4-(2-methylbenzyloxy)phenyl]guanidine

Salt: TFA×2

Mass: ES+ 411.4

Example 178 N-(3-Amino-2,2-dimethylpropyl)-4-benzyl-N′-[4-(3-trifluoromethoxybenzyloxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 569.3

Example 179 N-(3-Amino-2,2-dimethylpropyl)-3-methyl-N′-[4-(3-trifluoromethoxybenzyloxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 493.3

Example 180 N-(3-Amino-2,2-dimethylpropyl)-2-methyl-N′-[4-(3-trifluoromethoxybenzyl-oxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 493.3

Example 181 N-(3-Amino-2,2-dimethylpropyl)-2-ethyl-N′-[4-(3-trifluoromethoxybenzyloxy)-phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 507.3

Example 182 N-(3-Amino-2,2-dimethylpropyl)-4-benzyl-N′-[4-(4,4,4-trifluorobutoxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 505.4

Example 183 N-(3-Amino-2,2-dimethylpropyl)-4-methyl-N′-[4-(4,4,4-trifluorobutoxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 429.3

Example 184 N-(3-Amino-2,2-dimethylpropyl)-2-ethyl-N′-[4-(4,4,4-trifluorobutoxy)phenyl]-piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 443.4

Example 185 N-(3-Amino-2,2-dimethylpropyl)-4-benzyl-N′-(4-pentyloxyphenyl)piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 465.4

Example 186 N-(3-Amino-2,2-dimethylpropyl)-2-methyl-N′-(4-pentyloxyphenyl)piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 399.4

Example 187 N-(3-Amino-2,2-dimethylpropyl)-2-ethyl-N′-(4-pentyloxyphenyl)piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 403.4

Example 188 N-(3-Amino-2,2-dimethylpropyl)-4-benzyl-N′-[4-(4-methanesulfonylbenzyloxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 563.4

Example 189 N-(3-Amino-2,2-dimethylpropyl)-N′-[4-(4-methanesulfonylbenzyloxy)phenyl]-3-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 487.3

Example 190 N-(3-Amino-2,2-dimethylpropyl)-N′-[4-(4-methanesulfonylbenzyloxy)phenyl]-4-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 487.3

Example 191 N-(3-Amino-2,2-dimethylpropyl)-N′-[4-(4-methanesulfonylbenzyloxy)phenyl]-2-methylpiperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 487.3

Example 192 N-(3-Amino-2,2-dimethylpropyl)-2-ethyl-N′-[4-(4-methanesulfonylbenzyloxy)-phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 501.3

Example 193 N′-(3-Amino-2,2-dimethylpropyl)-N-ethyl-N-isopropyl-N″-[4-(4-methanesulfonylbenzyloxy)phenyl]guanidine

Salt: TFA×2

Mass: ES+ 475.3

Example 194 N-(3-Amino-2,2-dimethylpropyl)-4-benzyl-N′-[4-(4-trifluoromethoxybenzyloxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 569.4

Example 195 N-(3-Amino-2,2-dimethylpropyl)-4-methyl-N′-[4-(4-trifluoromethoxybenzyloxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 493.3

Example 196 N-(3-Amino-2,2-dimethylpropyl)-2-methyl-N′-[4-(4-trifluoromethoxybenzyloxy)phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 493.3

Example 197 N-(3-Amino-2,2-dimethylpropyl)-2-ethyl-N′-[4-(4-trifluoromethoxybenzyloxy)-phenyl]piperidine-1-carboxamidine

Salt: TFA×2

Mass: ES+ 507.4

Example 198 N′-(3-Amino-2,2-dimethylpropyl)-N-ethyl-N-isopropyl-N″-[4-(4-trifluoromethoxybenzyloxy)phenyl]guanidine

Salt: TFA×2

Mass: ES+ 481.3

Results

The activity of the compounds of the present invention is demonstrated in vitro in the following tests:

The stably transfected cell line (luciferase under the control of the human CETP promoter) is maintained in the growth medium (DMEM/Hepes, F12, Glutamax, FBS and geneticin) incubated at 37° C., 95% humidity and 5% CO₂ to the point of confluence. The cells are then rinsed with PBS and detached with a trypsin/EDTA mixture. The medium is changed every 2 to 3 days.

The resuspended cells are diluted and counted, and then distributed in microplate (96) wells.

About 20 000 cells per well are distributed and incubated overnight at 37° C. with 5% CO₂.

The compounds of the present invention are diluted to a final concentration of 15 μM and distributed in the plates containing the cells.

The plates are incubated overnight at 37° C. with 5% CO₂.

The medium covering the cells is drawn off and 100 μl of Steady Glo luciferase (DMEM without phenol red/Steady Glo, V/V) are added to the cells.

The plates are sealed with a film and left in the dark for about 20 minutes at room temperature.

The plates are then read using a luminometer (1 sec/well).

The inhibition of CETP expression by the products is expressed as a percentage of the control: ${\%\quad{CTRL}} = {\frac{{mean}\quad{product}\quad{CPS}}{{mean}\quad{control}\quad{CPS}} \times 100}$

By way of example, the activity expressed as a percentage of the control for the compounds of Examples 5, 31, 61 and 95 is 46%, 30%, 33% and 16%, respectively.

On another batch of plates not treated with Steady Glo, the state of the cultures is checked by microscope. The culture medium is removed and 100 μl of medium comprising neutral red are added for 3 hours at 37° C.

The medium is then removed and replaced for one minute with 100 μl of formaldehyde-calcium (10 ml of 37% formaldehyde+calcium chloride dihydrate 10 g qs 1 L).

The plate is emptied and 100 μl of acetic acid-ethanol mixture (10 ml of glacial acetic acid+500 ml of absolute ethanol qs 1 L) are added to each well for 15 minutes with stirring.

The plates are then read at 540 nm. The stronger the coloration, the greater the cellular toxicity.

No cellular toxicity is detected for the compounds of Examples 5, 31, 61 and 95. 

1. Compound of the formula (I):

in which: R¹ is chosen from a hydrogen atom and a (C₁-C₆)alkyl radical, or alternatively the two radicals R¹ form, together with the carbon atom that bears them, a (C₃-C₁₀)cycloalkyl radical; R² is chosen from a (C₁-C₁₀)alkyl radical, a (C₂-C₁₀)alkenyl radical, a (C₆-C₁₈)aryl(C₁-C₁₀)alkyl radical, a (C₁-C₆)alkyl-O—(C₁-C₁₀)alkyl radical and a (C₃-C₁₀)cycloalkyl(C₁-C₁₀)alkyl radical; R³ and R⁴, which may be identical or different, are chosen independently from a hydrogen atom, a (C₁-C₁₀)alkyl radical, a (C₂-C₁₀)alkenyl radical, a (C₆-C₁₈)aryl(C₁-C₁₀)alkyl radical, a (C₁-C₆)alkyl-O—(C₁-C₁₀)alkyl radical and a (C₃-C₁₀)cycloalkyl(C₁-C₁₀)alkyl radical, or alternatively R³ and R⁴ form, together with the nitrogen atom that bears them, a 3- to 9-membered heterocycle; R⁵, R⁶, R⁷ and R⁸, which may be identical or different, are chosen independently from a hydrogen atom, a (C₁-C₁₀)alkyl radical, a (C₁-C₁₀)alkenyl radical and a (C₁-C₆)alkyl-O— radical; and R⁰ and R¹⁰, which may be identical or different, are chosen independently from a hydrogen atom and a (C₁-C₆)alkyl radical, or alternatively R⁹and R¹⁰ form, together with the nitrogen atom that bears them, a 3- to 7-membered heterocycle; the optical and geometrical isomers, oxide forms and tautomeric forms thereof, and also the pharmaceutically acceptable addition salts thereof with acids or bases.
 2. Compound according to claim 1, in which the alkyl radicals possibly present are unsubstituted or monosubstituted and, in this case, more preferably ω-monosubstituted; the optical and geometrical isomers, oxide forms and tautomeric forms thereof and also the pharmaceutically acceptable addition salts thereof with acids or bases.
 3. Compound according to claim 1, for which R⁸ represents hydrogen; the optical and geometrical isomers, oxide forms and tautomeric forms thereof, and also the pharmaceutically acceptable addition salts thereof with acids or bases.
 4. Compound according to claim 1, for which R⁷ represents hydrogen; the optical and geometrical isomers, oxide forms and tautomeric forms thereof, and also the pharmaceutically acceptable addition salts thereof with acids or bases.
 5. Compound according to claim 1, for which R⁶ represents hydrogen; the optical and geometrical isomers, oxide forms and tautomeric forms thereof, and also the pharmaceutically acceptable addition salts thereof with acids or bases.
 6. Compound according to claim 1, for which R⁵ represents hydrogen; the optical and geometrical isomers, oxide forms and tautomeric forms thereof, and also the pharmaceutically acceptable addition salts thereof with acids or bases.
 7. Compound according to claim 1, for which R¹ represents a hydrogen atom or a (C₁-C₆)alkyl radical, preferably (C₁-C₃)alkyl and more preferably methyl; the optical and geometrical isomers, oxide forms and tautomeric forms thereof, and also the pharmaceutically acceptable addition salts thereof with acids or bases.
 8. Compound according to claim 1, for which R² is chosen from an unsubstituted (C₁-C₁₀)alkyl radical, an ω-monosubstituted (C₁-C₁₀)alkyl radical, a (C₂-C₁₀)alkenyl radical, a (C₆-C₁₈)aryl(C₁-C₁₀)-alkyl radical, preferably phenyl(C₁-C₁₀)alkyl, more preferably benzyl, more preferentially unsubstituted or monosubstituted on the aromatic nucleus, a (C₁-C₆)alkyl-O—(C₁-C₁₀)alkyl radical and a (C₃-C₁₀)cycloalkyl(C₁-C₁₀)alkyl radical, preferably (C₃-C₆)cycloalkyl(C₁-C₁₀)alkyl; the optical and geometrical isomers, oxide forms and tautomeric forms thereof, and also the pharmaceutically acceptable addition salts thereof with acids or bases.
 9. Compound according to claim 1, for which R⁹ and R¹⁰ are identical and each represent a hydrogen atom or a (C₁-C₆)alkyl radical, preferably a methyl radical; the optical and geometrical isomers, oxide forms and tautomeric forms thereof, and also the pharmaceutically acceptable addition salts thereof with acids or bases.
 10. Compound according to claim 1, for which R³ and R⁴ each represent a (C₁-C₆)alkyl radical, or alternatively R³ represents a hydrogen atom and R⁴ represents a (C₁-C₁₀)alkyl radical, or alternatively R³ and R⁴ form, together with the nitrogen atom that bears them, a 5- or 6-membered heterocycle; the optical and geometrical isomers, oxide forms and tautomeric forms thereof, and also the pharmaceutically acceptable addition salts thereof with acids or bases.
 11. Compound according to claim 1, having one or more of the following characteristics, taken separately or in combination: R¹ represents a hydrogen atom or a methyl radical; R² is chosen from an unsubstituted (C₁-C₁₀)alkyl radical, an ω-monosubstituted (C₁-C₁₀)alkyl radical, a (C₂-C₁₀)alkenyl radical, a phenyl(C₁-C₁₀)alkyl radical, preferably benzyl, more preferably unsubstituted or monosubstituted on the aromatic nucleus, a (C₁-C₆)alkyl-O—(C₁-C₁₀)alkyl radical and a (C₃-C₆)cycloalkyl(C₁-C₁₀)alkyl radical; R³ and R⁴ each represent a (C₁-C₆)alkyl radical, or alternatively R³ represents a hydrogen atom and R⁴ represents a (C₁-C₁₀)alkyl radical, or alternatively R³ and R⁴ form, together with the nitrogen atom that bears them, a 5- or 6-membered heterocycle; R⁵ represents hydrogen; R⁶ represents hydrogen; R⁷ represents hydrogen; R⁸ represents hydrogen; R⁹ and R¹⁰, which are identical, each represent a hydrogen atom or a methyl radical; the optical and geometrical isomers, oxide forms and tautomeric forms thereof, and also the pharmaceutically acceptable addition salts thereof with acids or bases.
 12. Compound according to claim 1, for which: R¹ represents a hydrogen atom or a methyl radical; R² is chosen from an unsubstituted (C₁-C₁₀)alkyl radical, an ω-monosubstituted (C₁-C₁₀)alkyl radical, a (C₂-C₁₀)alkenyl radical, a phenyl(C₁-C₁₀)alkyl radical, preferably benzyl, more preferably unsubstituted or monosubstituted on the aromatic nucleus, a (C₁-C₆)alkyl-O—(C₁-C₁₀)alkyl radical and a (C₃-C₆)cycloalkyl(C₁-C₁₀)alkyl radical; R³ and R⁴ each represent a (C₁-C₆)alkyl radical, or alternatively R³ represents a hydrogen atom and R⁴ represents a (C₁-C₁₀)alkyl radical, or alternatively R³ and R⁴ form, together with the nitrogen atom that bears them, a 5- or 6-membered heterocycle; R⁵, R⁶, R⁷ and R⁸ each represent a hydrogen atom; and R⁹ and R¹⁰, which are identical, each represent a hydrogen atom or a methyl radical; the optical and geometrical isomers, oxide forms and tautomeric forms thereof, and also the pharmaceutically acceptable addition salts thereof with acids or bases.
 13. Compound according to claim 1, chosen from: N-(3-Amino-2,2-dimethylpropyl)-N′-(4-benzyloxyphenyl)-N″-(3-methylbutyl)-guanidine bis(trifluoroacetate); N-(3-Aminopropyl)-2-methyl-N′-[4-(2-methylbenzyloxy)phenyl]piperidine-1-carboxamidine bis(trifluoroacetate); N-(3-Aminopropyl)-N′-(3-methylbutyl)-N″-(4-pentyloxyphenyl)guanidine bis(trifluoroacetate); N-(3-Aminopropyl)-N′-[4-(2-methoxyethoxyphenyl]-3-methylpiperidine-1-carboxamidine bis(trifluoroacetate); N-(3-Aminopropyl)-N′-[4-(2-methoxyethoxy)phenyl]-4-methylpiperidine-1-carboxamidine bis(trifluoroacetate); N′-(3-Aminopropyl)-N-ethyl-N-isopropyl-N″-[4-(2-methoxyethoxy)-phenyl]guanidine bis(trifluoroacetate); N-(3-Aminopropyl)-4-methyl-N′-[4-(3-methylbutoxy)phenyl]piperidine-1-carboxamidine bis(trifluoroacetate); N-(3-Aminopropyl)-2-methyl-N′-[4-(3-methylbutoxy)phenyl]piperidine-1-carboxamidine bis(trifluoroacetate); N-(3-Aminopropyl)-2-ethyl-N′-[4-(3-methylbutoxy)phenyl]piperidine-1-carboxamidine bis(trifluoroacetate); N-(3Aminopropyl)-N-ethyl-N-isopropyl-N″-[4-(3-methylbutoxy)phenyl]guanidine bis(trifluoroacetate); N-(3-Aminopropyl)-3-methyl-N′-(4-propoxyphenyl)piperidine-1-carboxamidine bis(trifluoroacetate); N-(3-Aminopropyl)-4-methyl-N′-(4-propoxyphenyl)piperidine-1-carboxamidine bis(trifluoroacetate); N-(3-Aminopropyl)-2-methyl-N′-(4-propoxyphenyl)piperidine-1-carboxamidine bis(trifluoroacetate); N-(3-Aminopropyl)-2-ethyl-N′-(4-propoxyphenyl)piperidine-1-carboxamidine bis(trifluoroacetate); N′-(3-Aminopropyl)-N-ethyl-N-isopropyl-N″-(4-propoxyphenyl)guanidine bis(trifluoroacetate); N(3Aminopropyl)-N′-[4-(4-tert-butylbenzyloxy)phenyl]-2-methylpiperidine-1-carboxamidine bis(trifluoroacetate); N-(3-Aminopropyl)-N′-[4-(4-tert-butylbenzyloxy)phenyl]-2-ethylpiperidine-1-carboxamidine bis(trifluoroacetate); N-(3-Aminopropyl)-4-benzyl-N′-[4-(4,4,4-trifluorobutoxy)phenyl]piperidine-1-carboxamidine bis(trifluoroacetate); N-(3-Aminopropyl)-2-ethyl-N′-(4-pentyloxyphenyl)piperidine-1-carboxamidine bis(trifluoroacetate); and N′-(3-Amino-2,2-dimethylpropyl)-N-ethyl-N-isopropyl-N″-[4-(2-methylbenzyloxy)phenyl]guanidine bis(trifluoroacetate), the optical and geometrical isomers, oxide forms and tautomeric forms thereof, and also the pharmaceutically acceptable addition salts thereof with acids or bases.
 14. Process for the preparation of the compounds of the general formula (I), according to synthetic scheme 3, in which the aryl thiocyanate (V) is subjected to the action of an amine HNR³R⁴, R³ and R⁴ being as defined in claim 1, in a polar protic medium, to give, after heating, the corresponding thiourea, which thiourea is then placed in a reducing medium with the amine of the formula (III) to give the compounds of the formula (I), which are isolated and purified, where appropriate.
 15. Process according to claim 14, for the preparation of the compounds of the general formula (I), for which R⁵, R⁶, R⁷ and R⁸ each represent a hydrogen atom.
 16. Process for the preparation of a compound according to claim 1, according to synthetic scheme 2, in which: the compound of the formula (II), in which:

represents a graft on resin, for example of Bromo Wang type; X is chosen from a hydrogen atom, a halogen atom, a (C₁-C₆)alkyl radical and a (C₁-C₆)alkoxy radical; is placed in contact with an excess of the amine of the formula (III) in an apolar aprotic solvent, for example dichloromethane, generally at room temperature, to give the compound of the formula (IV); the compound of the formula (IV) is then reacted, under conditions similar to those described above, with a compound of the formula (V), to give the thiourea of the formula (VI); the said thiourea (VI) is converted, by the action of an amine of the formula (VII), generally at room temperature, in a polar aprotic medium, for example DMF, and in the presence of mercuric salts, for example HgCl₂, to give the guanidine of the formula (VIII); the guanidine (VIII) is then detached from the resin, according to any technique known per se, for example using trifluoroacetic acid, dichloromethane and triisopropylsilane, to give the compounds of the formula (I_(A)), which are a special case of the compounds of the formula (I) for which R⁹ and R¹⁰ each represent a hydrogen atom; and the terminal amine of these compounds of the formula (I_(A)) may optionally be selectively mono- or dialkylated.
 17. Process according to claim 16, for the preparation of the compounds of the general formula (I), for which R⁴, R⁵, R⁶, R ⁷ and R⁸ each represent a hydrogen atom R³ represents an alkyl radical and R² represents a benzyl radical, according to synthetic scheme
 1. 18. Pharmaceutical composition comprising a pharmaceutically effective amount of at least one compound of the formula (I) according to claim 1, or obtained via a process of the invention, in combination with one or more pharmaceutically acceptable vehicles.
 19. Use of a compound of the formula (I) according to claim 1 or obtained via a process of the invention, for the preparation of a medicament for the prevention or treatment of dyslipidaemia, atherosclerosis and type II diabetes. 